Conventional means for delivering drugs are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself. Examples of physical barriers include the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain drugs but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
These barriers are of particular significance in the design of oral and transdermal delivery systems. Oral delivery of many drugs would be the route of choice for administration if not for biological, chemical, and physical barriers that prevent, restrict or reduce the passage of drugs. Transdermal delivery is also a desired method to deliver drugs that can pass through the skin. Among the numerous drugs that oral or transdermal delivery is desired include those which bind to amyloid and SAP, such as CPHPC and their salts or other drugs that treat Alzheimer's such as rivastigmine tartrate.
Amyloidosis is not a single disease but a term for diseases that share a common feature: the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues. Amyloid fibrils in primary amyloidosis are fragments of immunoglobulin light chains. There are different proteins making up the amyloid fibrils in reactive (secondary) amyloidosis and familial amyloidosis, and therefore specific therapies designed to target the source of fibril-precursor production.
The final pathway in the development of amyloidosis is the production of amyloid fibrils in the extracellular matrix. The process by which precursor proteins produce fibrils appears to be multifactorial and to differ among the various types of amyloid. In AL amyloidosis, the demonstration that substitutions of particular amino acids at specific positions in the light-chain variable region occur at significantly higher frequencies than in nonamyloid immunoglobulins has led to the suggestion that these replacements destabilize light chains, increasing the likelihood of fibrillogenesis.
In ATTR amyloidosis production of inherently unstable variant monomers of transthyrethin, produced by the substitution of amino acids, may allow the protein to precipitate when provoked by physical or chemical stimuli, resulting in the deposition of amyloid in organs in both AL and ATTR amyloidosis. These patients do not have clinically apparent disease until midlife, despite the lifelong presence of abnormal transthyretin, and have rapid progression and deterioration.
In addition, systemic amyloidosis is associated with hemodialysis and localized forms of amyloidosis are associated with Alzheimer's disease, Type II Diabetes, Medullary Carcinoma of the Thyroid and atrial amyloid deposition.
The treatment of amyloidosis is directed both toward the affected organ and to the specific type of the disease. Nephrotic disease is treated with diuretic therapy and dialysis. Congestive heart failure requires increasing doses of diuretics as cardiac disease progresses or renal function worsens. A subgroup of patients may benefit from implantation of a cardiac pacemaker. Neuropathy and gastrointestinal involvement are treated symptomatically. Gastromotility agents may be of some benefit. In familial Mediterranean fever, a genetic disorder associated with a high incidence of AA amyloidosis, therapy with colchicine specifically treats the underlying disease and prevents amyloidosis.
AL amyloidosis may be treated with chemotherapy; however, the response rate and survival rates are low with treatment with melphalan and prednisone. High dose therapy may provide substantial improvements in amyloid-related organ disease (hepatic, gastrointestinal, and neurological). The majority of patients with renal or cardiac involvement will also respond, with improved plasma cells and clinical symptoms.
In the small proportion of patients with AL amyloidosis that is limited to the heart, death is sudden or due to rapidly progressive heart failure. Cardiac transplantation has been performed in a few such patients, but progression in other organs or recurrence in the transplanted heart has occurred.
A limited number of patients with AL amyloidosis who receive chemotherapy with the iodinated anthracycline 4′-iodo-4′-deoxydoxorubicin had clinical benefit, and in vitro studies showed binding to amyloid fibrils and reduction of new deposits, but no reduction in circulating light chains could be documented
Liver transplantation and in a few patients with severe symptomatic cardiac involvement, combined liver and heart transplantation from a single donor has been performed with success.
Serum amyloid P compound, SAP, is found on the surface of all types of amyloid deposits, preventing the livers's ability to break down amyloid and its subsequent removal from the body. Drugs, such as CPHPC are being developed which may treat amyloidosis and diseases associated with deposition of amyloid.
CPHPC is currently an investigational drug used to sequester SAP and therefore reduce circulating amyloids and which may be successful for the treatment, or perhaps even cure of Alzheimer's disease. A goal of treatment is to reduce the amyloid level, increase excretion, but investigational studies indicate that CPHPC has poor oral bioavailability and would require administration via the parenteral route. Accordingly, there is a need for improved oral delivery systems for CPHPC which provide sufficient bioavailability to treat diseases associated with amyloid accumulation, such as Alzheimer's, Amyloidosis, and Diabetes. There is also a need for improved bioavailability of other active agents that treat Alzheimer's disease, such as rivastigmine tartrate.